Women who carry mutations in BRCA1 and BRCA2 (BRCA1/2) have a substantially increased risk of developing breast and ovarian cancers. There is considerable variability in age at diagnosis and relative incidence of breast and ovarian cancers, even among women with the same mutation, suggestive that additional risk factors modify the age-specific risk. We propose a comprehensive analysis of genes in the insulin-like growth factor (IGF) signaling pathway, a pathway integrally involved in cellular proliferation. We will use powerful new approaches that combine multiple linked variants in a single gene to form haplotypes and that allow evaluation of multiple genes in a single mechanistic pathway. We will utilize the resources of our multi-center cohort, which currently includes 2,000 Caucasian and 76 African-American BRCA1/2 female mutation carriers, and for which collection is ongoing. Few studies have been conducted in African Americans, even though they often have more aggressive breast cancer, present at a younger age, and have histopathology characteristic of BRCA1 tumors. Our overall objective is to identify genetic risk factors that modify breast cancer risk. Our specific aims are: Aim 1) to genotype Single Nucleotide Polymorphisms (SNPs) in IGF1, IGF1R, IGFBP1, IGFBP3, IRS1, and SHBG in 100 unrelated Caucasian and African Americans and identify haplotype blocks by linkage disequilibrium analysis. A subset of SNPs (haplotype-tagging SNPs and SNPs with known function) will be selected for Aim 3. Aim 2): to continue enrolling BRCAI/2 mutation carriers in order to expand our cohort. This includes extending previously enrolled families carrying mutations; continuing to enroll and screen African-American women with breast cancer and expanding families with deleterious mutations; and obtaining mutation carriers from our multi-center cohort. Aim 3: to genotype affected (cases) and unaffected (matched controls) BRCAI/2 mutation carriers for SNPs selected in Aim 1. Aim 4: to perform analyses to evaluate the role of the genotypes in breast cancer development, age at diagnosis and stage. Our focus is BRCA1/2 mutation carriers, who because of their higher risk of developing cancer at an early age, are the group for whom these results would be applied. This information can be used to assist women and their physicians in individual risk assessment, as well as to target women for specific prevention or treatment strategies based on their genetic risk factors.